tbuckley/cabot-search huggingface dataset:
Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/− long QT syndrome variant
Authors: Ravichandra Venkateshappa, Diana V Hunter, Priya Muralidharan, Raghu S Nagalingam, Galvin Huen, Shoaib Faizi, Shreya Luthra, Eric Lin, Yen May Cheng, Julia Hughes, Rania Khelifi, Daman Parduman Dhunna, Raj Johal, Valentine Sergeev, Sanam Shafaattalab, Lisa M Julian, Damon T Poburko, Zachary Laksman, Glen F Tibbits, Tom W Claydon
Journal: Cardiovascular Research (2023)

Abstract Aims Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR–Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243. Methods and results The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean action potential duration (APD90). However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of APD90 during rate transitions, and increases the incidence of 2:1 block. During paired S1–S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness. Conclusion Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.
Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood–brain barrier and exhibits potent activity against glioblastoma
Authors: Yingqiang Liu, Zhengsheng Zhan, Zhuang Kang, Mengyuan Li, Yongcong Lv, Shenglan Li, Linjiang Tong, Fang Feng, Yan Li, Mengge Zhang, Yaping Xue, Yi Chen, Tao Zhang, Peiran Song, Yi Su, Yanyan Shen, Yiming Sun, Xinying Yang, Yi Chen, Shanyan Yao, Hanyu Yang, Caixia Wang, Meiyu Geng, Wenbin Li, Wenhu Duan, Hua Xie, Jian Ding
Journal: Acta Pharmaceutica Sinica B (2023)

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).
Nasal epithelial gene expression and total IgE in children and adolescents with asthma
Authors: Zhongli Xu, Erick Forno, Yidan Sun, Michelle L. Manni, Yueh Ying Han, Soyeon Kim, Molin Yue, Judith M. Vonk, Elin T.M. Kersten, Edna Acosta-Perez, Glorisa Canino, Gerard H. Koppelman, Wei Chen, Juan C. Celedón
Journal: Journal of Allergy and Clinical Immunology (2023)
Nanomotor-based H2S donor with mitochondrial targeting function for treatment of Parkinson's disease
Authors: Zinan Zhao, Lin Chen, Chunhao Yang, Wenyan Guo, Yali Huang, Wenjing Wang, Mimi Wan, Chun Mao, Jian Shen
Journal: Bioactive Materials (2023)

Reduction of endogenous hydrogen sulfide (H2S) is considered to have an important impact on the progress of Parkinson's disease (PD), thus exogenous H2S supplementation is expected to become one of the key means to treat PD. However, at present, it is difficult for H2S donors to effectively penetrate the blood brain barrier (BBB), selectively release H2S in brain, and effectively target the mitochondria of neuron cells. Herein, we report a kind of nanomotor-based H2S donor, which is obtained by free radical polymerization reaction between l-cysteine derivative modified-polyethylene glycol (PEG-Cys) and 2-methacryloyloxyethyl phosphorylcholine (MPC). This kind of H2S donor can not only effectively break through BBB, but also be specifically catalyzed by cystathionine β-synthase (CBS) in neurons of PD site in brain and 3-mercaptopyruvate sulfurtransferase (3-MST) in mitochondria to produce H2S, endowing it with chemotaxis/motion ability. Moreover, the unique chemotaxis effect of nanomotor can realize the purpose of precisely targeting brain and the mitochondria of damaged neuron cytopathic diseases. This kind of nanomotor-based H2S donor is expected to enrich the current types of H2S donors and provide new ideas for the treatment of PD.
Glioblastoma cell invasion: Go? Grow? Yes
Authors: David J Odde
Journal: Neuro-Oncology (2023)

Journal Article Glioblastoma cell invasion: Go? Grow? Yes Get access David J Odde David J Odde Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA Corresponding Author: David Odde, PhD, Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA (oddex002@umn.edu) https://orcid.org/0000-0001-7731-2799 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 12, December 2023, Pages 2163–2164, https://doi.org/10.1093/neuonc/noad178 Published: 22 September 2023 Article history Published: 22 September 2023 Corrected and typeset: 17 October 2023
Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis
Authors: Megha Rajasekhar, Julie A Simpson, Benedikt Ley, Peta Edler, Cindy S Chu, Tesfay Abreha, Ghulam R Awab, J Kevin Baird, Germana Bancone, Bridget E Barber, Matthew J Grigg, Jimee Hwang, Harin Karunajeewa, Marcus V G Lacerda, Simone Ladeia-Andrade, Alejandro Llanos-Cuentas, Sasithon Pukrittayakamee, Komal R Rijal, Kavitha Saravu, Inge Sutanto, Walter R J Taylor, Kamala Thriemer, James A Watson, Philippe J Guerin, Nicholas J White, Ric N Price, Robert J Commons, Bipin Adhikari, Mohammad Shafiul Alam, Nicholas M Anstey, Ashenafi Assefa, Sarah C Boyd, Nguyen Hoang Chau, Nicholas PJ Day, Tamiru Shibiru Degaga, Arjen M Dondorp, Marcelo Urbano Ferreira, Prakash Ghimire, Justin A Green, Wasif Ali Khan, Gavin CKW Koh, Asrat Hailu Mekuria, Mohammad Nader Naadim, Erni J Nelwan, Francois Nosten, Ayodhia Pitaloka Pasaribu, David J Price, Kasia Stepniewska, Lorenz von Seidlein, Timothy William, Charles J Woodrow, Adugna Woyessa
Journal: The Lancet Infectious Diseases (2023)

Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.
Expanding the feasibility of large genomic skin studies using epidermal DNA collected via tape stripping
Authors: Amanda E Toland
Journal: British Journal of Dermatology (2023)

Journal Article Corrected proof Expanding the feasibility of large genomic skin studies using epidermal DNA collected via tape stripping Get access Amanda E Toland Amanda E Toland Writing - original draft, Writing - review & editing Departments of Cancer Biology and Genetics and Internal Medicine, Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA Email: Amanda.toland@osumc.edu https://orcid.org/0000-0002-0271-1792 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad360, https://doi.org/10.1093/bjd/ljad360 Published: 22 September 2023 Article history Received: 14 September 2023 Accepted: 17 September 2023 Published: 22 September 2023 Corrected and typeset: 01 November 2023
Brain tumors in United States military veterans
Authors: John R Bihn, Gino Cioffi, Kristin A Waite, Carol Kruchko, Corey Neff, Mackenzie Price, Quinn T Ostrom, Kaitlin N Swinnerton, Danne C Elbers, Michael A Mooney, Jacob Rachlin, Thor D Stein, Mary T Brophy, Nhan V Do, Ryan E Ferguson, David S Priemer, Daniel P Perl, Richard A Hickman, Burt Nabors, Jennifer Rusiecki, Jill S Barnholtz-Sloan, Nathanael R Fillmore
Journal: Neuro-Oncology (2023)

Abstract Background Comprehensive analysis of brain tumor incidence and survival in the Veteran population has been lacking. Methods Veteran data were obtained from the Veterans Health Administration (VHA) Medical Centers via VHA Corporate Data Warehouse. Brain tumor statistics on the overall US population were generated from the Central Brain Tumor Registry of the US data. Cases were individuals (≥18 years) with a primary brain tumor, diagnosed between 2004 and 2018. The average annual age-adjusted incidence rates (AAIR) and 95% confidence intervals were estimated per 100 000 population and Kaplan–Meier survival curves evaluated overall survival outcomes among Veterans. Results The Veteran population was primarily white (78%), male (93%), and between 60 and 64 years old (18%). Individuals with a primary brain tumor in the general US population were mainly female (59%) and between 18 and 49 years old (28%). The overall AAIR of primary brain tumors from 2004 to 2018 within the Veterans Affairs cancer registry was 11.6. Nonmalignant tumors were more common than malignant tumors (AAIR:7.19 vs 4.42). The most diagnosed tumors in Veterans were nonmalignant pituitary tumors (AAIR:2.96), nonmalignant meningioma (AAIR:2.62), and glioblastoma (AAIR:1.96). In the Veteran population, survival outcomes became worse with age and were lowest among individuals diagnosed with glioblastoma. Conclusions Differences between Veteran and US populations can be broadly attributed to demographic composition differences of these groups. Prior to this, there have been no reports on national-level incidence rates and survival outcomes for Veterans. These data provide vital information that can drive efforts to understand disease burden and improve outcomes for individuals with primary brain tumors.
TCRαβ/CD19 cell–depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis
Authors: Pietro Merli, Mattia Algeri, Federica Galaverna, Valentina Bertaina, Barbarella Lucarelli, Emilia Boccieri, Marco Becilli, Francesco Quagliarella, Chiara Rosignoli, Simone Biagini, Elia Girolami, Antonella Meschini, Giovanna Del Principe, Raffaella Sborgia, Maria Luigia Catanoso, Roberto Carta, Luisa Strocchio, Rita Maria Pinto, Barbara Buldini, Michela Falco, Raffaella Meazza, Daniela Pende, Marco Andreani, Giuseppina Li Pira, Daria Pagliara, Franco Locatelli
Journal: Blood (2023)
EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma
Authors: Yunxia Liu, Shuichi Kimpara, Nguyet M. Hoang, Anusara Daenthanasanmak, Yangguang Li, Li Lu, Vu N. Ngo, Paul D. Bates, Longzhen Song, Xiaoyue Gao, Samantha Bebel, Madelyn Chen, Ruoyu Chen, Xiyu Zhang, Paul E. Selberg, Vaishalee P. Kenkre, Thomas A. Waldmann, Christian M. Capitini, Lixin Rui
Journal: Blood (2023)
Optimizing preclinical pediatric low-grade glioma models for meaningful clinical translation
Authors: Till Milde, Jason Fangusaro, Michael J Fisher, Cynthia Hawkins, Fausto J Rodriguez, Uri Tabori, Olaf Witt, Yuan Zhu, David H Gutmann
Journal: Neuro-Oncology (2023)

Abstract Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in young children. While they are typically associated with good overall survival, children with these central nervous system tumors often experience chronic tumor- and therapy-related morbidities. Moreover, individuals with unresectable tumors frequently have multiple recurrences and persistent neurological symptoms. Deep molecular analyses of pLGGs reveal that they are caused by genetic alterations that converge on a single mitogenic pathway (MEK/ERK), but their growth is heavily influenced by nonneoplastic cells (neurons, T cells, microglia) in their local microenvironment. The interplay between neoplastic cell MEK/ERK pathway activation and stromal cell support necessitates the use of predictive preclinical models to identify the most promising drug candidates for clinical evaluation. As part of a series of white papers focused on pLGGs, we discuss the current status of preclinical pLGG modeling, with the goal of improving clinical translation for children with these common brain tumors.
Reinforced antimyeloma therapy via dual-lymphoid activation mediated by a panel of antibodies armed with bridging-BiTE
Authors: Tatsuya Konishi, Toshiki Ochi, Masaki Maruta, Kazushi Tanimoto, Yukihiro Miyazaki, Chika Iwamoto, Takashi Saitou, Takeshi Imamura, Masaki Yasukawa, Katsuto Takenaka
Journal: Blood (2023)
Natural history study of patients with familial platelet disorder with associated myeloid malignancy
Authors: Lea Cunningham, Matthew Merguerian, Katherine R. Calvo, Joie Davis, Natalie T. Deuitch, Alina Dulau-Florea, Nisha Patel, Kai Yu, Keith Sacco, Sumona Bhattacharya, Monica Passi, Neval Ozkaya, Seila De Leon, Shawn Chong, Kathleen Craft, Jamie Diemer, Erica Bresciani, Kevin O’Brien, Elizabeth J. Andrews, Nguyen Park, Londa Hathaway, Edward W. Cowen, Theo Heller, Kerry Ryan, Amisha Barochia, Khanh Nghiem, Julie Niemela, Sergio Rosenzweig, David J. Young, Pamela A. Frischmeyer-Guerrerio, Raul Braylan, Paul P. Liu
Journal: Blood (2023)
National Prevalence of Diabetes and Barriers to Care Among U.S. Farmworkers and Association With Migrant Worker Status
Authors: Rose McKeon Olson, Cody P. Nolan, Neha Limaye, Miriam Osei, Daniel Palazuelos
Journal: Diabetes Care (2023)

To quantify the prevalence of diabetes and barriers to care among U.S. migrant farmworkers (i.e., those who travel from their permanent residence for seasonal farmwork).Age-adjusted prevalence of self-reported diabetes and barriers to care were calculated among adult U.S. farmworkers from 2008 to 2017 National Agricultural Workers Surveys.Among 16,913 farmworkers, 30.7% reported one or more barriers to care, most often due to cost. Age-adjusted self-reported prevalence of diabetes was 13.51% (95% CI 10.0-17.1) among migrant farmworkers and 10.8% (95% CI 9.0-12.6) among nonmigrant farmworkers with access to health care. Migrant farmworkers without recent health care had 83% lower odds of reporting known diabetes (adjusted odds ratio 0.17; 95% CI 0.06-0.54) compared with nonmigrant farmworkers, likely because of poor health care access and/or a healthy worker effect.Many migrant farmworkers face barriers to care, which may lead to significant underdiagnosis of diabetes in this vulnerable population.
Detecting Episodic Evolution through Bayesian Inference of Molecular Clock Models
Authors: John H Tay, Guy Baele, Sebastian Duchene
Journal: Molecular Biology and Evolution (2023)

Molecular evolutionary rate variation is a key aspect of the evolution of many organisms that can be modeled using molecular clock models. For example, fixed local clocks revealed the role of episodic evolution in the emergence of SARS-CoV-2 variants of concern. Like all statistical models, however, the reliability of such inferences is contingent on an assessment of statistical evidence. We present a novel Bayesian phylogenetic approach for detecting episodic evolution. It consists of computing Bayes factors, as the ratio of posterior and prior odds of evolutionary rate increases, effectively quantifying support for the effect size. We conducted an extensive simulation study to illustrate the power of this method and benchmarked it to formal model comparison of a range of molecular clock models using (log) marginal likelihood estimation, and to inference under a random local clock model. Quantifying support for the effect size has higher sensitivity than formal model testing and is straight-forward to compute, because it only needs samples from the posterior and prior distribution. However, formal model testing has the advantage of accommodating a wide range molecular clock models. We also assessed the ability of an automated approach, known as the random local clock, where branches under episodic evolution may be detected without their a priori definition. In an empirical analysis of a data set of SARS-CoV-2 genomes, we find "very strong" evidence for episodic evolution. Our results provide guidelines and practical methods for Bayesian detection of episodic evolution, as well as avenues for further research into this phenomenon.
Disease burden, comorbidities and antecedents of chronic cough phenotypes in Australian adults
Authors: S. Suresh, J.L. Perret, E.H. Walters, M.J. Abramson, G. Bowatte, C. Lodge, A. Lowe, B. Erbas, P. Thomas, G.S. Hamilton, A.B. Chang, S.C. Dharmage, D.S. Bui
Journal: Pulmonology (2023)

While adult chronic cough has high burden, its phenotypes, particularly those without aetiologically related underlying conditions, are understudied. We investigated the prevalence, lung function and comorbidities of adult chronic cough phenotypes. Data from 3608 participants aged 53 years from the Tasmanian Longitudinal Health Study (TAHS) were included. Chronic cough was defined as cough on most days for >3 months in a year. Chronic cough was classified into "explained cough" if there were any one of four major cough-associated conditions (asthma, COPD, gastroesophageal reflux disease or rhinosinusitis) or "unexplained cough" if none were present. Adjusted regression analyses investigated associations between these chronic cough phenotypes, lung function and non-respiratory comorbidities at 53 years. The prevalence of chronic cough was 10% (95%CI 9.1,11.0%) with 46.4% being "unexplained". Participants with unexplained chronic cough had lower FEV1/FVC (coefficient: -1.2% [95%CI:-2,3, -0.1]) and increased odds of comorbidities including obesity (OR=1.6 [95%CI: 1.2, 2.3]), depression (OR=1.4 [95%CI: 1.0, 2.1]), hypertension (OR=1.7 [95%CI: 1.2, 2.4]) and angina, heart attack or myocardial infarction to a lesser extent, compared to those without chronic cough. Participants with explained chronic cough also had lower lung function than both those with unexplained chronic cough and those without chronic cough. Chronic cough is prevalent in middle-age and a high proportion is unexplained. Unexplained cough contributes to poor lung function and increased comorbidities. Given unexplained chronic cough is not a symptom of major underlying respiratory conditions it should be targeted for better understanding in both clinical settings and research.
Emerging Therapies in Hypothyroidism
Authors: Antonio C. Bianco
Journal: Annual Review of Medicine (2023)

Levothyroxine (LT4) is effective for most patients with hypothyroidism. However, a minority of the patients remain symptomatic despite the normalization of serum thyrotropin levels. Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone. Many patients who do not fully benefit from LT4 experience improved quality of life and cognition after switching to LT4+LT3. For these patients, new slow-release LT3 formulations that provide stable serum T3 levels are being tested. In addition, progress in regenerative technology has led to the development of human thyroid organoids that restore euthyroidism after being transplanted into hypothyroid mice. Finally, there is a new understanding that, under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved. This is seen, for example, in patients with metabolic (dysfunction)-associated fatty liver disease, for whom liver-selective T3-like molecules have been utilized successfully in clinical trials.
Management of Resistant Hypertension
Authors: Lucas Lauder, Felix Mahfoud, Michael Böhm
Journal: Annual Review of Medicine (2023)

Resistant hypertension (RH) is a severe form of hypertension associated with increased cardiovascular risk. Although true RH affects less than 10% of the patients receiving antihypertensive therapy, the absolute number is high and continues to increase. The workup of these patients requires screening for secondary hypertension and pseudoresistance, including poor adherence to prescribed medicines and the white-coat phenomenon. The treatment of RH consists of lifestyle modifications and pharmacological therapies. Lifestyle modifications include dietary adjustments, weight loss, physical activity, and limiting alcohol consumption; pharmacological therapies include diuretics, mineralocorticoid receptor antagonists, beta blockers, angiotensin receptor–neprilysin inhibitors, and others. Over the last 15 years, interventional approaches have emerged as adjunct treatment options; we highlight catheter-based renal denervation. This review summarizes the rationales and latest clinical evidence and, based thereon, proposes an updated algorithm for the management of RH.
Mass Spectrometry–Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine
Authors: Sunil K. Joshi, Paul Piehowski, Tao Liu, Sara J.C. Gosline, Jason E. McDermott, Brian J. Druker, Elie Traer, Jeffrey W. Tyner, Anupriya Agarwal, Cristina E. Tognon, Karin D. Rodland
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.